 Hello again to everyone and my name is Maria Victoria Mateos, hematologist at the University Hospital of Salamanca in Spain. And thanks again to my Loma patients in Europe for inviting me to this meeting. And I will address now the topic of immunotherapy in the treatment of patients with multiple myeloma as well as amyloidosis. Here you can see my conflict of interest and maybe something that you know is that one of the hallmarks of cancer is to try to avoid the immune destruction. And this is a mechanism that it is very common in almost all cancers, but is this concept also applicable to multiple myeloma? And you have to know that the answer is yes, because here in this picture you can see how the plasma cells in yellow try to proliferate. And in order to proliferate they create an environment completely immunosuppressed. And the T lymphocytes and the B lymphocytes do not work very well because plasma cells want to be the key players in order to proliferate. And throughout when we utilize the immunotherapy, what we are going to utilize is the power of all these immune cells in order to try to attack the plasma cells proliferated in the bone marrow. And you have to know that the immunotherapy is not something completely new in multiple myeloma. And in fact the allogenic stencil transplantation was one of the first concepts in which the normal lymphocytes are trying to attack the plasma cells. Interferon was also a very old drug utilized in patients with multiple myeloma and the immunomodulatory drugs have also this immunomodulatory effect. Here you can see plasma cell bone marrow microenvironment with the different targets that we can utilize as immunotherapy in multiple myeloma. And the first one is CD38. CD38 is quite commonly expressed on the surface of the plasma cells and it is possible to attack it throughout the monoclonal antibody data tumor mava with a direct anti tumor activity but also with an immunomodulatory effect. And a direct tumor mava was the first monoclonal antibody so far approved in multiple myeloma as single agent. But isatuximab is another anti-CD38 monoclonal antibody with a similar but not completely identical mechanism of action. And these monoclonal antibodies emerge for the treatment of patients with multiple myeloma because when myeloma patients had been already treated with proteasome inhibitors and immunomodulatory drugs and they were refractory to bortesumid, carfilumid, lenalidomide and pomalidomide the outcome was quite poor. And a direct tumor mava but this is also applicable to isatuximab were able to cover this un-medical neither. And you know for example right now how direct tumor mava is presented across the different stage of the disease. Since later found the stage of the disease in the first and second relapse even in the Afron setting in combination with the standard of curves and even in the smaller in myeloma population. As I previously told you in the other talk. This is an example data tumor mava in combination with VMP in the newly diagnosed myeloma patients in this case transplant in a legible with a benefit not only in terms of progression for survival but also in overall survival. And the same is applicable to data in combination with the lenalidomide and examedasone with a very important benefit in progression for survival. And at European hematology association congress we had the opportunity to see how this combination resulted also into a benefit in overall survival. But this is not only applicable to patients with multiple myeloma but also to patients with amyloidosis and a data tumor mava in combination with the standard of care. CYBORDY has been evaluated in the phase three and Romeda study conducted in patients with primary amyloidosis with a significant benefit. And in fact that this is important for you patients data tumor mava in combination with CYBORDY has been the first combination so far approved for the patients with primary amyloidosis. And the rationale for the approval is the higher hematological complete response rate observed when data was added to CYBORDY. This was the primary endpoint but in addition the probability the higher probability for achieving hematological complete response rate was observed in all different subgroup of patients. Even patients with advanced stage of the disease with cardiac involvement with kidney involvement and even when the 1114 translocation was also present. This is translated also into one benefit in terms of what we call overall response rate. But I think that it is very important to evaluate the complete response rate that it was the primary endpoint and especially the progression of survival. This is a modified progression of survival but definitely puts in context that when we add data tumor mava to CYBORDY the response is going to be better. And the durability of the response is going to be longer and this is translated into this benefit in terms of progression for survival. And isatopsimava is a similar anti-CV38 monoclonal antibody that is also under investigation in late advanced stage of the disease in combination with pomalidomide and dexamidazone carfilzomide in the first line of therapy and even also in smothering myeloma patients. So CYB38 as target has been crucial in order to establish the role of immunotherapy in multiple myeloma and CYB38 are taking part over the treatment of our patients with multiple myeloma. Another target is this is what you can see here islam F7 and we can target this target with ilotusumava. This is another monoclonal antibody with a dual mechanism of action but at the end of the day the killing of the plasma cells is going to occur. However, when ilotusumava was evaluated as single agent, ilotusumava doesn't work. Ilotusumava needs to be combined with immunomodulatory agents like lenalidomide or pomalidomide because when this combination occurs, there is going to be a potentiation of the immune cells in order to destroy the plasma cells. And this has been observed in this phase three randomized study and ilotusumava in combination with lenalidomide and dexamidazone is a standard of care we can utilize not in all European countries but in most of them in combination with lenalidomide and dexamidazone. But also it is possible to combine pomalidomide with ilotusumava and this phase two randomized study showed a significant benefit also for this combination. Where are we going to use these other monoclonal antibodies like ilotusumava in combination with lenalidomide and dexamidazone? Basically in the relapse and refractory situation, in first relapse, in second or third relapse in combination with lenalidomide or pomalidomide. And I would like to say that in principle ilotusumava will not be utilized as part of the first line of therapy. If we continue with this slide evaluating other potential targets for immunotherapy in multiple myeloma, we have to go to BCMA. And BCMA is one of the newest targets expressed on the surface of the plasma cell that we can attack throughout immunotherapy strategies and we can utilize antibody drug conjugators, T-cell engagers or bi-specific monoclonal antibodies or decartes. And I would like to briefly explain in which well how this novel immunotherapy strategies work in patients with multiple myeloma. And in principle and first of all why we need this BCMA targeted therapy. If I showed you how after bortesumibocarpilum, lenalidomide and pomalidomide, anti-CD38 emerges. But when patients exhausted also the anti-CD38 monoclonal antibodies, the survival is quite poor. And in principle there is not any standard of care in order to rescue patients already treated with these conventional agents. And this is basically the rationale for the generation of new standard of care, like in this case, BCMA targeted therapy. The first strategy are immunoconjugated monoclonal antibodies. And these monoclonal antibodies is represented by the Belantama Fodotin already approved by the European Medical Agency for the treatment of relapse and refractory myeloma patients. And the mechanism of action is basically the release of a cytotoxic agent within the plasma cell resulting into the killing of the plasma cell. And Belantama Fodotin demonstrated to be effective in a series of approximately 100 relapsing refractory myeloma patients, all of them what we call triple refractory. So they were refractory to proteasome inhibitors in monomodulatory drugs and anti-CD38 monoclonal antibodies. And in this situation Belantama Fodotin was effective. We have to take care about the safety profile because the toxicity profile is new. It's an induced thrombocytopenia and it's quite manageable as well as ocular toxicity instead in terms of keratopathy. But it is quite frequent observed in over 70% of the patients. But however, you have to see that the symptomatology the patient prefer is observed as a dry eye or blood vision in no many patients, no more than approximately 20% of the patients. And what is important, it is reversible and over 90% of the patients recover this toxicity. And it's quite manageable with those interruptions as well as production of the doses with no impact in the quality of life. And I would like to remark that the capacity of the patients receiving Belantama for driving or for reading ordinary printer while they were receiving on treatment was not important by the treatment with Belantama Fodotin. How are we going to integrate Belantama Fodotin in the treatment of patients with multiple myeloma? You know that today is allocated to this triple refractory myeloma patients or in principle those patients already exposed to proteasomy inhibitors in its as well as anti-CD38 monoclonal antibodies. But this is the summary for Belantama Fodotin and the second step is to go to the cartis. And you know that the cartis are also quite effective. You know that the BCMA cartis means that we have to extract the lymphocytes from the patients. These lymphocytes are going to be genetically modified in order to deliver to our patients these lymphocytes modified with a signal in order to go directly to attack the BCMA express on the surface of the plasma cells. And BCMA cartis resulted very effective because in this meta-analysis in which the outcome for more than 600 patients with myeloma treated with BCMA carti was analyzed overall the overall respirator was 80%. And this means that this therapy is very effective. This is ID cell, the first BCMA cartis so far approved by FDA. And we are awaiting the approval here in Europe with very positive data in terms of overall respirator as well as a progression for survival and even overall survival. And the same is applicable to this P-votal phase 2 CARMA study. This trial will result into the approval of ID cell here in Europe. And again, you can see how 128 relapsing refractory myeloma patients already exposed to six prior lines of therapy responded very well to ID cell with a quite long durability of the response. And important to remark that the efficacy was maintained in patients with high risk features. Those patients with extramedular disease, plasma cytomas or a highly cytogenetic abnormalities or a high tumor burden and all these patients responded very well to the BCMA cartis. And the chronological age should not be any problem because you have to know that patients older than 65 and even older than 70 were included in these clinical trials and the efficacy was maintained. This is another BCMA carti, Phil Tafel also updated at ASCO and EHA Congress conducted in approximately 100 patients with a very promising efficacy data because the overall respirator was almost 100%. This means that every patient treated with Phil Tafel achieved at least partial response and the complete respirator was almost 70%. This is the outcome in terms of progression for survival and overall survival also quite long and definitely unexpected for the population included in these clinical studies. And we had the opportunity to see an update at EHA as well as ASCO in order to see how the median progression for survival could be longer than two years what is unprecedented for the population included in the study. Safety profile is also different. You know that the BCMA carti administration may require right now and especially in Europe hospitalization for two, three weeks. And we have to take care about the cytokine release syndrome frequent in almost all patients but quite manageable. We have to take care about the neurological toxicity but it is much less frequent than the cytokine release syndrome and it is also quite manageable in almost all patients. Cytopenias are also quite frequent but this is something that we know very well how to manage and you as patients have to receive adequate prophylaxis for bacterial fungal virus in order to prevent the infections development. But this is something important for you as patients. The quality of life the patients have reported in the clinical trials with BCMA cartis has been excellent and the treatment expectation as well as the comparison with the previous myeloma treatment is excellent. You have to know and maybe you know that the BCMA cartis requires the single infusion. There is not any additional treatment following the carti cell administration and this can also impact in the quality of life but also because of the efficacy almost all patients respond and this definitely translated into an excellent quality of life. And together with the antibody drug conjugators as well as the cartis I have to present to you the bi-specific monoclonal antibodies or the T cell engagers. And I think that the T cell engagers is a very appropriate word because these monoclonal antibodies are going to target the BCMA but they are going to engage the T cell in order to go to the tumor niche. These T lymphocytes are going to be activated and they are going to destroy the plasma cells. And there is a long list of bi-specific or T cell engagers monoclonal antibodies and you can see here in this list six different BCMA bi-specific monoclonal antibodies. The most important thing is that all of them work quite well in heavily treated myeloma patients. And this is very important because these are going to represent again another possibility to cover the medical need that we had when we had in front of us patients after a million of six prior lines of therapy already exposed and refractory to proteasome inhibitors in immunomodulatory drugs and anti-CD38 monoclonal antibodies. From the safety point of view, well, you have to know that the cytokine release syndrome is also present in these monoclonal antibodies. Because when these T lymphocytes are active, they liberate the release cytokines responsible of this symptomatology. Neurotoxicity can occur but is less frequent than with the CAR-T as well as infections, but you are space and will receive the adequate prophylaxis. How are we going to differentiate all these long list of T cell engagers? Well, we don't know. We have to evaluate very well the efficacy, but we will compare them basically because of the root of administration. Some of them require IV, some of them SACU. You have to know that for the administration of these T cell engagers, at the beginning you can't require hospitalization for the first doses in order to mitigate the cytokine release syndrome. But anyway, I think that these bi-specific monoclonal antibodies will open the door to be treated with another different strategy than CAR-T, but targeting again BCMA. And this is a summary slide just in order to show how BCMA is an optimal target for multiple myeloma patients. We can target BCMA throughout immunoconjugators, bi-specific or CAR-T, and you can see here some advantages and disadvantages for each of these approaches. Because you know that immunoconjugators are bi-specific are off the shelf and these drugs are going to be in the pharmacy of each hospital available to be utilized in each moment, whilst CAR-T is much more personalized. And you know that we have to collect the T lymphocytes and they have to be manufactured, they have to be modified. And this process requires approximately four or five weeks. But be sure that your physician will take into consideration these factors you can see here in this slide. The frailty, the disease morbidity, the risk assessment, the treatment history, and the lifestyle in order to select the most appropriate BCMA targeted therapy for each specific patient. If we have to look a bit into the future, just to mention that the Belantamapmaphositin is being investigated in combination with many standard of course, with botesomib, pomalidomide, carfilsomib, and so on. So we will have the possibility of using in the future Belantamapmap in combination with many different standard of course. If we evaluate a bit the BCMA CAR-Ts or the CAR-Ts in general into the future, you have to know that many clinical trials are going on in order to try to optimize the efficacy of the BCMA CAR-Ts. And we will have new targets, new modalities, and definitely this will open the possibility of building a curative platform for patients with multiple myeloma. I'm concerning the biospecifics and beyond CD38, SLAM-F7, and BCMA new targets in order to evaluate immunotherapy in myeloma. GPR-C5D is also expressed on the surface of the plasma cells as well as in the hair follicle and talcetamab is a T cell engager, but in this case it is not going to target BCMA but the GPR-C5D. And the efficacy is quite impressive also with this biospecific monoclonal antibody. And this is another new biospecific monoclonal antibody. Its name is Fevostamab and the target is FCR-H5 and also the efficacy is quite promising. So in summary I would say that the immunotherapy is exciting for the management of patients with multiple myeloma. Now this BCMA targeted therapy is restricted to late advanced stage of the disease but definitely all these strategies are moving to earlier lines of therapy. And maybe the challenging question in terms of the future is what would the optimal sequencing be? And from my personal point of view, I think that every newly diagnosed myeloma patient in the future will be treated with proteasome inhibitors in monomodulatory drugs and anti-CD38 monoclonal antibodies. And definitely it is possible to move this BCMA targeted therapy throughout valentamuffin combination, CAR T cells or T cell engagers to earlier lines of therapy. And definitely all these platforms will put in context that we will be able to offer at least long-term survival for our patients with multiple myeloma. But I am completely sure that we will be able to offer the cure to some patients with multiple myeloma. And I stop here. Thank you very much for your attention.